Bottom Line:
Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior.These results provide a link between cocaine use and problems with insight.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

Affiliation: 1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

ABSTRACTAddiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

Figure 1: Experimental timeline, task design and recording sites for in vivo recordingexperimenta. Timeline and task design. Approximately 3 weeks after the end ofself-administration, rats were trained in a Pavlovian over-expectation task while singleunit activity was recorded in OFC. b. Drawings illustrate recording sites inOFC in sucrose (blue) and cocaine-trained (red) rats. Boxes indicate approximate locationof recording sites in each rat, taking into account any vertical distance traveled duringtraining and the approximate lateral spread of the electrode bundle.

Mentions:
Rats were trained (n=8) to self-administer cocaine for 3-h/day for 14days using a fixed ratio 1, 40-sec timeout schedule of reinforcement that has beenassociated with cardinal behaviors, such as relapse and incubation of cocaine craving,thought to be important models of addiction 14, 15; control rats (n=12)were trained to respond for oral sucrose (a potent non-drug reward in rodents) usingidentical procedures (Fig.S1a–b). Three weeks after the end of self-administration, we recordedsingle-unit activity from the orbitofrontal cortex (OFC) in these rats as they weretrained in a Pavlovian over-expectation task 16, used previously to study orbitofrontal function 6, 17 (Fig. 1a and Table S1). This task consists of three phases:initial conditioning, compound training, and extinction testing. In initial conditioning,rats are trained that each of several different cues predicts the same amount of reward inthe same location. In subsequent compound training, two of the cues are presentedtogether, still followed by the same reward. Normal rats show increased responding to thiscompound cue – termed summation – that is thought to reflect a novel andimmediate expectation for increased reward. As operationalized above, this increasedexpectation requires insight, because past experience does not directly dictate thatgreater reward should result when both cues occur simultaneously. Furthermore, because thecompound cue yields the same reward as each individual cue, the novel expectation resultsin a prediction error and hence new learning, as evidenced by an immediate decline inresponding to the one of the compounded cues when it is presented later, by itself, in theextinction test. Both summation and the resultant learning are dependent on the OFC17, secondary to a sudden increasein activity in pyramidal neurons in this area during presentation of the compound cues6. These data suggest that the OFCgenerates the novel estimates and insight into likely outcomes upon which both summationand learning depend.

Figure 1: Experimental timeline, task design and recording sites for in vivo recordingexperimenta. Timeline and task design. Approximately 3 weeks after the end ofself-administration, rats were trained in a Pavlovian over-expectation task while singleunit activity was recorded in OFC. b. Drawings illustrate recording sites inOFC in sucrose (blue) and cocaine-trained (red) rats. Boxes indicate approximate locationof recording sites in each rat, taking into account any vertical distance traveled duringtraining and the approximate lateral spread of the electrode bundle.

Mentions:
Rats were trained (n=8) to self-administer cocaine for 3-h/day for 14days using a fixed ratio 1, 40-sec timeout schedule of reinforcement that has beenassociated with cardinal behaviors, such as relapse and incubation of cocaine craving,thought to be important models of addiction 14, 15; control rats (n=12)were trained to respond for oral sucrose (a potent non-drug reward in rodents) usingidentical procedures (Fig.S1a–b). Three weeks after the end of self-administration, we recordedsingle-unit activity from the orbitofrontal cortex (OFC) in these rats as they weretrained in a Pavlovian over-expectation task 16, used previously to study orbitofrontal function 6, 17 (Fig. 1a and Table S1). This task consists of three phases:initial conditioning, compound training, and extinction testing. In initial conditioning,rats are trained that each of several different cues predicts the same amount of reward inthe same location. In subsequent compound training, two of the cues are presentedtogether, still followed by the same reward. Normal rats show increased responding to thiscompound cue – termed summation – that is thought to reflect a novel andimmediate expectation for increased reward. As operationalized above, this increasedexpectation requires insight, because past experience does not directly dictate thatgreater reward should result when both cues occur simultaneously. Furthermore, because thecompound cue yields the same reward as each individual cue, the novel expectation resultsin a prediction error and hence new learning, as evidenced by an immediate decline inresponding to the one of the compounded cues when it is presented later, by itself, in theextinction test. Both summation and the resultant learning are dependent on the OFC17, secondary to a sudden increasein activity in pyramidal neurons in this area during presentation of the compound cues6. These data suggest that the OFCgenerates the novel estimates and insight into likely outcomes upon which both summationand learning depend.

Bottom Line:
Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior.These results provide a link between cocaine use and problems with insight.As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.

Affiliation:
1] National Institute on Drug Abuse Intramural Research Program, Baltimore, Maryland, USA. [2] Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland, USA.

ABSTRACTAddiction is characterized by a lack of insight into the likely outcomes of one's behavior. Insight, or the ability to imagine outcomes, is evident when outcomes have not been directly experienced. Using this concept, work in both rats and humans has recently identified neural correlates of insight in the medial and orbital prefrontal cortices. We found that these correlates were selectively abolished in rats by cocaine self-administration. Their abolition was associated with behavioral deficits and reduced synaptic efficacy in orbitofrontal cortex, the reversal of which by optogenetic activation restored normal behavior. These results provide a link between cocaine use and problems with insight. Deficits in these functions are likely to be particularly important for problems such as drug relapse, in which behavior fails to account for likely adverse outcomes. As such, our data provide a neural target for therapeutic approaches to address these defining long-term effects of drug use.